Biochemistry and nutrition for USMLE Step 1

A 6-month-old infant presents with hepatomegaly, hypoglycemia after short fasts, lactic acidosis, hyperuricemia and hyperlipidemia. Muscle strength is normal. Liver biopsy shows markedly increased glycogen with normal structure. Which enzyme is most likely deficient?

1. Glucose-6-phosphatase correct Correct. Von Gierke disease (type I). Without glucose-6-phosphatase the liver cannot release free glucose from either glycogenolysis or gluconeogenesis, so fasting hypoglycemia is severe and early, and the blocked pathway diverts substrate to lactate, urate and triglyceride.
2. Branching enzyme Andersen disease presents with cirrhosis and failure to thrive from abnormally branched glycogen. The biopsy here shows structurally normal glycogen.
3. Muscle glycogen phosphorylase McArdle disease affects muscle only: exercise intolerance, cramps, myoglobinuria and a flat lactate response to exercise. Liver and blood glucose are normal.
4. Debranching enzyme Cori disease gives milder fasting hypoglycemia with abnormally structured glycogen and, importantly, normal lactate because gluconeogenesis is intact.
5. Lysosomal acid alpha-1,4-glucosidase Pompe disease, which pumps up the heart: cardiomegaly, hypotonia, early death. Blood glucose is characteristically normal because cytoplasmic glycogen handling is intact.

The point: Sort glycogen storage diseases by organ and by whether lactate rises. Type I: liver, severe fasting hypoglycemia, HIGH lactate. Type III: milder, normal lactate. Type V: muscle only. Type II: heart.

Source: USMLE Content Outline — biochemistry and nutrition NBME / FSMB (USMLE programme) · tier 0, exam blueprint / regulator

A 3-year-old boy has coarse facial features, corneal clouding, hepatosplenomegaly and developmental delay. Urinary glycosaminoglycans are elevated. A second boy has the same features except that his corneas are CLEAR and he has severe behavioural disturbance. Which enzyme is deficient in the second boy?

1. Hexosaminidase A Tay–Sachs: cherry-red macula with NO hepatosplenomegaly, which is the discriminator from Niemann–Pick.
2. Beta-glucocerebrosidase Gaucher disease: hepatosplenomegaly, bone crises and crumpled-tissue-paper macrophages, without glycosaminoglycanuria.
3. Sphingomyelinase Niemann–Pick: cherry-red macula, hepatosplenomegaly, foam cells. Again not a mucopolysaccharidosis.
4. Alpha-L-iduronidase Hurler syndrome (MPS I), autosomal recessive, with CORNEAL CLOUDING. That is the first boy.
5. Iduronate sulfatase correct Correct. Hunter syndrome (MPS II) is X-linked, spares the cornea and is marked by aggressive behaviour. The mnemonic that survives the exam: Hunters need clear sight to aim, and they are aggressive.

The point: Both mucopolysaccharidoses give coarse features and airway and joint disease. Hurler: alpha-L-iduronidase, AR, cloudy cornea. Hunter: iduronate sulfatase, X-linked, clear cornea, aggression.

Source: USMLE Content Outline — biochemistry and nutrition NBME / FSMB (USMLE programme) · tier 0, exam blueprint / regulator

A 24-year-old man of Mediterranean descent develops jaundice, dark urine and a hemoglobin fall from 14 to 8.5 g/dL three days after starting primaquine. The blood film shows bite cells and Heinz bodies. Which biochemical consequence of the enzyme defect explains the hemolysis?

1. Defective spectrin in the membrane skeleton Hereditary spherocytosis: spherocytes, raised MCHC, positive osmotic fragility, splenomegaly, not drug-triggered.
2. Failure of ATP production by glycolysis That is pyruvate kinase deficiency, which gives chronic hemolysis from birth rather than episodic oxidant-triggered hemolysis, and no Heinz bodies.
3. Absent GPI anchors for CD55 and CD59 Paroxysmal nocturnal hemoglobinuria, with complement-mediated intravascular hemolysis and thrombosis, diagnosed by flow cytometry.
4. Failure to regenerate NADPH, so glutathione cannot be kept reduced correct Correct. Glucose-6-phosphate dehydrogenase is the rate-limiting step of the pentose phosphate pathway and the red cell's only source of NADPH. Without reduced glutathione, oxidised hemoglobin precipitates as Heinz bodies and splenic macrophages bite them out.
5. Reduced beta-globin chain synthesis Beta-thalassemia: microcytic anemia with target cells and a raised HbA2, present lifelong rather than after a drug.

The point: G6PD deficiency is X-linked. Triggers: primaquine, dapsone, sulfonamides, nitrofurantoin, fava beans, and infection. Which is the commonest trigger of all. Test AFTER the episode; during hemolysis the surviving young cells give a falsely normal level.

Source: USMLE Content Outline — biochemistry and hematology NBME / FSMB (USMLE programme) · tier 0, exam blueprint / regulator